Its pathology, immunoregulatory abnormalities, response to immunosuppression and similarity to animal autoimmune models are compatible with multiple sclerosis (MS) being at least in part an autoimmune disease. Two myelin specific proteins, basic protein (MBP), and proteolipid protein (PLP) are capable of inducing a chronic, often relapsing, inflammatory and demyelinating disease in animals. They are therefore major candidates for the antigens involved in MS. Since experiments in animals have demonstrated that treatments for EAE can be based on knowledge of antigen epitopes and T-cell receptor usage, it is important that the antigen(s) involved in MS be identified. We and others have demonstrated the presence of myelin-antigen specific T cells in the peripheral blood of MS subjects and controls. Our past efforts on the immunology of PLP led to the realization that PLP, like MBP would induce experimental allergic encephalomyelitis. Based on our hypothesis that T-cells recognizing PLP may have a role in the pathogenesis of MS, we propose several experiments to determine differences between myelin-specific T cells in peripheral blood and cerebrospinal fluid among MS and control subjects. We have preliminary data suggesting a much higher prevalence and frequency of these cells in MS compared to control subjects. The proposed studies will confirm these data and expand them to include serial frequency analysis studies on individuals. In addition, with the help of collaborators, we propose to isolate lymphocytes from blood, CSF, and CNS tissues from MS patients and control subjects and to compare antigenic specificities, HLA restriction, T cell receptors, cytotoxicity, surface proteins and cytokine production of myelin-specific T cell clones to identify potentially pathogenic cells.